Mitochondrial dysfunction is a common occurrence in the aging process and is observed in diseases such as age-related macular degeneration (AMD). Increased levels of reactive oxygen species lead to ...damaged mitochondrial DNA (mtDNA), resulting in dysfunctional mitochondria, and, consequently, mtDNA causes further harm in the retinal tissue. However, it is unclear whether the effects are locally restricted to the high-energy-demanding retinal pigment epithelium or are also systematically present. Therefore, we measured mtDNA copy number (mtDNA-CN) in peripheral blood using a qPCR approach with plasmid normalization in elderly participants with and without AMD from the AugUR study (n = 2262). We found significantly lower mtDNA-CN in the blood of participants with early (n = 453) and late (n = 170) AMD compared to AMD-free participants (n = 1630). In regression analyses, we found lower mtDNA-CN to be associated with late AMD when compared with AMD-free participants. Each reduction of mtDNA-CN by one standard deviation increased the risk for late AMD by 24%. This association was most pronounced in geographic atrophy (OR = 1.76, 95% CI 1.19–2.60, p = 0.004), which has limited treatment options. These findings provide new insights into the relationship between mtDNA-CN in blood and AMD, suggesting that it may serve as a more accessible biomarker than mtDNA-CN in the retina.
Mitochondrial DNA copy number (mtDNA-CN) is a biomarker for mitochondrial dysfunction associated with several diseases. Previous genome-wide association studies (GWAS) have been performed to unravel ...underlying mechanisms of mtDNA-CN regulation. However, the identified gene regions explain only a small fraction of mtDNA-CN variability. Most of this data has been estimated from microarrays based on various pipelines. In the present study we aimed to (1) identify genetic loci for qPCR-measured mtDNA-CN from three studies (16,130 participants) using GWAS, (2) identify potential systematic differences between our qPCR derived mtDNA-CN measurements compared to the published microarray intensity-based estimates, and (3) disentangle the nuclear from mitochondrial regulation of the mtDNA-CN phenotype. We identified two genome-wide significant autosomal loci associated with qPCR-measured mtDNA-CN: at HBS1L (rs4895440, p = 3.39 × 10
) and GSDMA (rs56030650, p = 4.85 × 10
) genes. Moreover, 113/115 of the previously published SNPs identified by microarray-based analyses were significantly equivalent with our findings. In our study, the mitochondrial genome itself contributed only marginally to mtDNA-CN regulation as we only detected a single rare mitochondrial variant associated with mtDNA-CN. Furthermore, we incorporated mitochondrial haplogroups into our analyses to explore their potential impact on mtDNA-CN. However, our findings indicate that they do not exert any significant influence on our results.
Oxidative stress (OS) and inflammation are features of metabolic syndrome (MetS) that can contribute to the shortening of telomere length (TL), a marker of cellular ageing. Research indicates that ...exercise can positively influence MetS-associated conditions and TL. However, the effects of low-volume exercise types on TL are still unknown. We investigated the impact of very-low-volume high-intensity interval training (LV-HIIT), one-set resistance training (1-RT), and whole-body electromyostimulation (WB-EMS) on TL, inflammation, and cardiometabolic indices in 167 MetS patients. Data were derived from two randomized controlled trials where patients were allocated to an exercise group (2 sessions/week, for 12 weeks) or a control group. All groups received standard-care nutritional weight loss counselling. TL was determined as the T/S ratio (telomere to single-copy gene amount). All groups significantly reduced body weight (p < 0.05), but the T/S-ratio (p < 0.001) only increased with LV-HIIT. OS-related inflammatory markers (C-reactive protein, interleukin-6, and lipopolysaccharide-binding protein) only decreased (p < 0.05) following LV-HIIT. The MetS severity z-score improved with LV-HIIT (p < 0.001) and 1-RT (p = 0.014) but not with WB-EMS. In conclusion, very-low-volume exercise modalities have differential effects on telomeres, inflammation, and cardiometabolic health. Only LV-HIIT but not strength-based low-volume exercise increased TL in MetS patients, presumably due to superior effects on OS-related inflammatory markers.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. A few earlier genome-wide association studies (GWAS) investigated genetic variants associated with ...circulating PCSK9 concentrations. However, uncertainty remains about some of the genetic loci discovered beyond the PCSK9 locus. By conducting the largest PCSK9 meta-analysis of GWAS (meta-GWAS) so far, we aimed to identify novel loci and validate the previously reported loci that regulate PCSK9 concentrations.
We performed GWAS for PCSK9 concentrations in two large cohorts (GCKD (n = 4,963) and KORA F3 (n = 2,895)). These were meta-analyzed with previously published data encompassing together 20,579 individuals. We further conducted a second meta-analysis in statin-naïve individuals (n = 15,390). A genetic risk score (GRS) was constructed on PCSK9-increasing SNPs and assessed its impact on the risk for coronary artery disease (CAD) in 394,943 statin-naïve participants (17,077 with events) of the UK Biobank by performing CAD-free survival analysis.
Nine loci were genome-wide significantly associated with PCSK9 concentrations. These included the previously described PCSK9, APOB, KCNA1/KCNA5, and TM6SF2/SUGP1 loci. All imputed SNPs in the PCSK9 locus account for ∼15% of variance of PCSK9 concentrations. We further identified FADS2 as a novel locus that was also found in statin-naïve participants. All imputed SNPs within the FADS2 locus explain ∼1.2% of variance of PCSK9 concentrations. Additionally, four further loci (a region on chromosome 5, SDK1, SPATA16 and HPR) were genome-wide significant in either the main model or the statin-naïve subset. The linear increase in a PCSK9 genetic risk score was associated with 1.41-fold (95%CI 1.16-1.72, p < 0.001) higher risk for incident CAD.
We identified five novel loci (FADS2, SPATA16, SDK1, HPR and a region on chromosome 5) for PCSK9 concentrations that would require further research. Additionally, we confirm the genome-wide significant loci that were previously detected.
Relative telomere length (RTL) is a biomarker for physiological aging. Premature shortening of telomeres is associated with oxidative stress, which is one possible pathway that might contribute to ...age-related macular degeneration (AMD). We therefore aimed to investigate the association between RTL and AMD in a well-characterized group of elderly individuals.
We measured RTL in participants of the AugUR study using a multiplex quantitative PCR-based assay determining the ratio between the telomere product and a single-copy gene product (T/S ratio). AMD was assessed by manual grading of color fundus images using the Three Continent AMD Consortium Severity Scale.
Among the 2262 individuals 70 to 95 years old (627 with AMD and 1635 without AMD), RTL was significantly shorter in individuals with AMD compared to AMD-free participants. In age- and sex-adjusted logistic regression analyses, we observed an 8% higher odds for AMD per 0.1 unit shorter RTL (odds ratio OR = 1.08; 95% confidence interval CI, 1.02-1.14; P = 0.005). The estimates remained stable when adjusted for smoking, high-density lipoprotein cholesterol, cardiovascular disease, diabetes, and hypertension. Interestingly, this association was only present in women (OR = 1.14; 95% CI, 1.06-1.23; P < 0.001), but not in men (OR = 1.01; 95% CI, 0.93-1.10; P = 0.76). A significant sex-by-RTL interaction on AMD was detected (P = 0.043).
Our results show an association of RTL with AMD that was restricted to women. This is in line with altered reactive oxygen species levels and higher telomerase activity in women and provides an indication for a sex-differential pathway for oxidative stress and AMD.
Sarcopenia is defined as an age-associated loss of skeletal muscle function and muscle mass and is common in older adults. Sarcopenia as a disease is currently of interest not only to orthopedists ...and surgeons but also to internists, endocrinologists, rheumatologists, cardiologists, diabetologists, gynaecologists, geriatricians and paediatricians. In cooperation with the 5th Internal Medicine Clinic, we, as a unit of clinical research, aimed to describe a sarcopenic specific miRNA expression profile for disease diagnostics and classification of the severity of muscle performance deterioration. This study included a total of 80 patients (age 55-86 years) hospitalized at the V. Internal medicine clinic of LFUK and UNB with different severity of muscle performance deterioration. The study participants were evaluated and classified according to short physical performance battery score (SPPB). In this study, we investigated the role of circulating miRNAs in sarcopenia in the elderly. We hypothesized that sarcopenia effects the expression of muscle tissue-specific miRNAs (MyomiRNAs), which could be potentially reflected in the blood plasma miRNA expression profile. The expression of specific circulating miRNAs in patients with different muscle performances was analyzed. Patients' blood plasma was evaluated for the expression of myomiRNAs: miRNA-29a, miRNA-29b, miRNA-1, miRNA-133a, miRNA-133b, miRNA-206, miRNA-208b and miRNA-499, and the data were correlated with diagnostic indicators of the disease. We showed a specific sarcopenia miRNA profile that could be considered a possible biomarker for the disease. Patients with low muscle performance showed increased miRNA-1, miRNA-29a and miRNA-29b expression and decreased for the miRNA-206, miRNA-133a, miRNA-133b, miRNA-208b and miRNA-499 expression. We show that the severity of muscle performance deterioration in sarcopenia correlates with specific miRNA expression. We also propose the profile of miRNAs expression in blood plasma as a specific biomarker for sarcopenia diagnostics. Future clinical studies will be necessary to eventually naturally have to elucidate the underlined molecular mechanism responsible for specific miRNAs expression in sarcopenia pathology and progression of the disease.
•Halomonas halophila was identified as auspicious halophilic PHA producer.•Morphology and cell diameters depends on PHA content.•Properties of produced materials can be tailored by manipulating NaCl ...concentration.•Bacterium can produce PHA from various inexpensive and waste resources.
This work explores molecular, morphological as well as biotechnological features of the highly promising polyhydroxyalkanoates (PHA) producer Halomonas halophila. Unlike many other halophiles, this bacterium does not require expensive complex media components and it is capable to accumulate high intracellular poly(3-hydroxybutyrate) (PHB) fractions up to 82% of cell dry mass. Most remarkably, regulating the concentration of NaCl apart from PHB yields influences also the polymer’s molecular mass and polydispersity. The bacterium metabolizes various carbohydrates including sugars predominant in lignocelluloses and other inexpensive substrates. Therefore, the bacterium was employed for PHB production on hydrolysates of cheese whey, spent coffee grounds, sawdust and corn stover, which were hydrolyzed by HCl; required salinity of cultivation media was set up during neutralization by NaOH. The bacterium was capable to use all the tested hydrolysates as well as sugar beet molasses for PHB biosynthesis, indicating its potential for industrial PHB production.
Microbial poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) bio-polyester was combined by thermoforming with Kraft lignin in order to design new advanced composite materials for packaging purpose. ...After assessing the compatibility of the two raw materials, the thermoformed composite sheets were investigated in order to assess the impact of the lignin fraction (between 0 and 10wt.%) on melting and crystallization behavior, thermo-oxidative stability, mechanical and viscoelastic properties, and permeability for oxygen and carbon dioxide. It turned out that the applied Kraft lignin is highly compatible with microbial PHBHV, and by exerting a reinforcing effect, acts as an active additive. As aspired, the gas permeability was decreased by combining PHBHV with 1wt.% lignin; here, a reduction of permeability for oxygen by 77% and by 91% for carbon dioxide, respectively, was observed if compared to the native bio-polyester specimens. Also the low thermo-oxidation stability, a typical characteristic of pure PHBHV, was increased for the lignin-containing materials. This first report on thermoformed composite materials of microbial PHBHV and lignin suggests a new class of bio-based polymer materials to be applied for packaging of various easily perishable goods.
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•Evolved strains demonstrated better growth in the presence of LA.•Adaptation of C. necator H16 to LA led to higher content of 3HV in P(3HB-co-3HV).•Higher 3HV content was connected ...with lower crystallinity and lower Tm.•Slightly different adaptation strategies of evolved strains were observed.•PCA has been used for multiparametric analysis of data.
Evolutionary engineering is an approach, which allows preparing microorganisms with desired phenotype without the need for knowledge of genetic characteristics connected with changes at phenotype level. This approach is based on cell multiplication under stress conditions and it can be performed in various designs. In connection with PHA-producing bacteria, evolutionary engineering can be used to gain microorganisms producing PHAs with required material properties. Using levulinic acid (LA) as a stress factor and Cupriavidus necator H16 as a model PHA producing bacterial strain, five evolved strains have been obtained in the present study. Compared with the parental strain, all of these showed better growth in the presence of LA, strains ALA01 and ALA04 showed higher PHA content in biomass and strains ALA03 and ALA04 showed higher 3-hydroxyvalerate (3HV) content in copolymer P(3HB-co-3HV). By DSC and FTIR analysis of polymers, connections between 3HV content, crystallinity and melting temperature have been studied. Metabolic characterization provided information about possible adaptation strategies of evolved strains, while based on methods of statistical analysis similarities and differences between individual strains were discussed. Considering obtained information, evolutionary engineering displays a useful tool for modification of microorganisms together with fine-tuning the properties of produced metabolites (PHA copolyesters).
The differentiation of hematopoietic stem cells into cells of the immune system has been studied extensively in mammals, but the transcriptional circuitry that controls it is still only partially ...understood. Here, the Immunological Genome Project gene-expression profiles across mouse immune lineages allowed us to systematically analyze these circuits. To analyze this data set we developed Ontogenet, an algorithm for reconstructing lineage-specific regulation from gene-expression profiles across lineages. Using Ontogenet, we found differentiation stage-specific regulators of mouse hematopoiesis and identified many known hematopoietic regulators and 175 previously unknown candidate regulators, as well as their target genes and the cell types in which they act. Among the previously unknown regulators, we emphasize the role of ETV5 in the differentiation of γδ T cells. As the transcriptional programs of human and mouse cells are highly conserved, it is likely that many lessons learned from the mouse model apply to humans.
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